AI-based structure prediction empowers integrative structural analysis of human nuclear pores

Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport. Their intricate 120-megadalton architecture remains incompletely understood. Here, we report a 70-megadalton model of the human NPC scaffold with explicit membrane and in multiple conformational states. We combined artificial intelligence (AI)-based structure prediction with in situ and in cellulo cryo-electron tomography and integrative modeling. We show that linker nucleoporins spatially organize the scaffold within and across subcomplexes to establish the higher-order structure. Microsecond-long molecular dynamics simulations suggest that the scaffold is not required to stabilize the inner and outer nuclear membrane fusion but rather widens the central pore. Our work exemplifies how AI-based modeling can be integrated with in situ structural biology to understand subcellular architecture across spatial organization levels.

Automated summary

This study combines artificial intelligence-based structure prediction with in situ structural biology to reveal the structure and function of the human nuclear pore complex (NPC) scaffold. The findings demonstrate the importance of linker nucleoporins in establishing the higher-order structure of the scaffold and suggest that it widens the central pore rather than stabilizing the fusion of the inner and outer nuclear membranes.